# Thyroid-Stimulating Hormone Regulates the Glucose Metabolism in Hepatocytes via Toll-Like Receptor 4/Tollip Pathway

## TL;DR

This study shows that thyroid-stimulating hormone affects liver cell glucose metabolism through a pathway involving TLR4 and Tollip.

## Contribution

The paper identifies a novel TSH/TSHR-regulated pathway involving TLR4 and Tollip in hepatocyte glucose metabolism.

## Key findings

- TSH activates TLR4 signaling and inhibits glucose metabolism in hepatocytes.
- Silencing TSHR or TLR4 rescues glucose metabolism, indicating their regulatory role.
- TSH reduces Tollip expression, and Tollip silencing increases TLR4 activity and reduces glucose metabolism.

## Abstract

Metabolic disorders are closely associated with thyroid dysfunction and the activity of thyroid-stimulating hormone (TSH). Previously, we found that subclinical hypothyroidism aggravates Toll-like receptor 4 (TLR4) signaling and interferes with glucose metabolism in rat liver tissue. Here, we explored the underlying mechanisms by which TSH affected TLR4 and glucose metabolism on hepatocytes in vitro. Hepatocytes were stimulated with TSH (0, 5, 10, and 20 mIU/mL) for 12 h and mRNA level of its receptor, thyroid-stimulating hormone receptor (TSHR), was increased. In contrast, glucose metabolism was blocked. After blocking TSHR, glucose metabolism in hepatocytes was rescued. Additionally, TSH treatment also activated TLRs signaling, and the expression of TLR4 and its downstream partners all decreased after TSHR was silenced, which indicated that TSH promotes TLR4 signaling through a TSHR-dependent mechanism. For the exploitation of the underlying relationship between TLR4 and glucose metabolism, siRNA was utilized to silence TLR4. After silencing TLR4, glucose metabolism was significantly rescued, which indicated that TLR4 was involved in the TSH-mediated downregulation of glucose metabolism in hepatocytes. Furthermore, as for the inhibitor of TLRs, Tollip was also measured. Under TSH treatment, the expression level of Tollip decreases. After silencing Tollip, TLR4 and its partners significantly increased and glucose metabolism was reduced. Our study indicated that TSH/TSHR regulated hepatocellular glucose metabolism via the TLR4/Tollip pathway.